1. Field of the Invention
The present invention pertains at least in part to cancer, chemical compounds, their preparation, formulation, and use in treating conditions such as cancer.
2. Description of the Related Art
RSK has emerged as an anti-cancer target. Ribosomal S6 protein kinases (RSKs) are a family of highly conserved protein serine/threonine kinases that includes subfamilies p90 RSK and p70 RSK and belong to the AGC super family. T. L. Nguyen, Anti-Cancer Agents in Medicinal Chemistry, 8, 710-716 (2008); Y. Romeo et al., Expert Opin. Ther. Targets, 15(1):5-9 (2011).
There are four isoforms of p90 RSK (RSK 1-4) in vertebrates, which exhibit variable tissue expression, and are activated in response to growth factors, polypeptide hormones, neurotransmitters, and chemokines. RSK lies downstream of the MAPK signaling pathway and is directly phosphorylated by ERK1/2. RSK activation was also found to be triggered by p38 and ERK5, and FGFR3. RSK regulates cellular processes such as cell growth, motility, survival, and proliferation. Nguyen, Romeo, above.
RSK contributes to antiapoptosis signaling by phosphorylating BAD, C/EBPβ, and DAP kinase. RSK is a mediator of FGFR3, being phosphorylated by it, and RSK is a regulator in cell transformations induced by tumor promoters. Some RSK substrates are themselves cancer targets of interest, such as Myt1 and GSK-3. Nguyen, Romeo, above.
Deregulated RSK expression or activity has been associated with several diseases, including cancers such as breast, multiple myeloma, acute myeloid leukemia, hand and neck cancer, osteosarcoma, and prostate. RSK has been linked to HIV and Coffin-Lowry syndrome (CLS), caused by a mutation in RSK2. A cardiovascular target of RSK is NHE1 and thus RSK inhibitors may be useful in treating cardiovascular disease.
RSK may be a promising target for treating cancers characterized by oncogenic Ras/MAPK signaling; and RSK2 has been the isoform most closely linked with human cancers. Nguyen, Romeo, above.
Compounds disclosed as inhibitors of RSK have come from various chemotypes. J. A. Smith et al., Cancer Res., 65(3), 1027-1034 (2005); Nguyen, above. The dihydropteridinone BI-D1870 was found to be a potent inhibitor of RSK1-4. G. P. Sapkota et al., Biochem J., 401, 29-38 (2007).
The reader may also take note of: U.S. Pat. No. 5,424,311; U.S. Pat. No. 6,806,272; U.S. Pat. No. 7,169,778; U.S. Pat. No. 7,759,347; US2002/0086866; US2006/0047118; US2007/0155730; US2008/0194572; US2009/0124628; US2010/0216726; US2011/0124634; WO2001/019825; WO2005/018531; WO2005/123736; WO2006/021547; WO2007/014838; WO2007/135374; WO2008/009909; WO2008/040951; WO2008/092831; WO2008/093075; WO2009/139834; WO2010/080712; WO2011/016472; WO2011/036566; EP0590428.
There is a need for effective therapies for use in proliferative disease, including treatments for primary cancers, prevention of metastatic disease, and targeted therapies, including tyrosine kinase inhibitors, such as RSK, including its individual isoforms. Thus, problems addressed by the present invention include the identification of potent and selective RSK inhibitors that further preferably possess other generally desirable drug-like physico-chemical and biological properties.